At the present time protection from anthrax exposure is largely based upon vaccination of those considered at risk, particularly including active duty military personnel in combat theaters, veterinarians in certain settings, and laboratory workers. The anti-Protective Antigen (PA) antibody level is widely considered the most easily accessible surrogate for a protective response from anthrax infection. We propose to apply the modern reverse genetics approach to this immune response in an effort to understand the genetic contributors to this vaccine response, in particular, and in the anticipation that genetic variants important in the response to anthrax will also be important in other successful vaccinations. To our knowledge modern reverse genetic tools have not been previously applied to develop a basic understanding of the genetic contribution to any vaccination, much less to anthrax. In three preliminary studies supported during the first grant cycle we have evaluated the relationship between the quantitative levels of anti-PA antibodies to 500,000 single nucleotide polymorphisms (SNPs) covering the autosomes and X chromosome in over 300 participants vaccinated with Anthrax Vaccine Absorbed (AVA). A number of candidate genes have been thereby identified, which warrant replication and fine mapping studies, the first of which is underway. We propose to expand the scope of the genome scan to 1,500,000 screening SNPs, and also to perform replication and fine mapping studies, to secure the participation of a total of 4000 vaccinated subjects, and to evaluate the genomics of the resulting genes. While it has taken a considerable effort to collect the samples necessary for this analysis, with samples now in hand, preliminary data available, and a now constant stream of new samples, the project is now ripe for substantial progress. The results of the project should identify many new genes important for the future development of vaccines and for understanding resistance to lethal anthrax.